Quantitative Measurement of Isotope Ratios at the part-per-trillion Level by TOF MS Summary This project is aimed at developing and demonstrating the performance of a new multi-stage laser desorption time-of-flight mass spectrometer that provides accurate measurement of the relative abundance of isotopes at very low levels. This instrument will ultimately provide performance at least equal to that achieved by established methods employing accelerator mass spectrometers at a very small fraction of the cost. The proposed benchtop instrument is small, highly automated and suitable for use by relatively untrained operators in a hospital or medical research laboratory. The major focus in this work is on those applications that require measurements of specific isotopes at levels below the part-per-billion level. These applications generally involve radioactive isotopes with very long half-lives (>1000 years). Specific examples include 14C for radiocarbon dating and biological tracer studies, and 41Ca used as a tracer for monitoring bone long term metabolic status in human patients. These applications often require precise determination of the relative abundance of isotopes at levels below 10-10 and extending down to 10-15. At present these measurements require use of a very large and expensive "accelerator mass spectrometer" (AMS) located in a central facility. Accelerator mass spectrometry has demonstrated the utility of long- lived radioisotopes as biological tracers, but applications have been limited by the relatively high cost and inaccessibility of complex instruments housed in central facilities. Nevertheless, support from the NIH, the pharmaceutical industry, and several AMS-based businesses led to a 2006 FDA guidance statement including AMS-based 14C microdosing (i.e., first-in-human "Phase 0" studies) of drug pharmacokinetics and pharmacodynamics, and AMS studies of 41Ca for cancer diagnostics have also seen early support from the NIH. The technique is limited to solid samples deposited on a suitable target, and it appears that the sample preparation procedures that have been developed for AMS can be employed with little or no modification in the proposed instrument. PUBLIC HEALTH RELEVANCE: Building on the basic scientific work conducted using accelerator mass spectrometry (AMS), this project will enable broader application of these state-of-the-art research and diagnostic methods by providing inexpensive instruments with competitive performance that are suitable for routine use in clinical and medical research laboratories. For example, measurement of the ratio of 41Ca/Ca in urine and serum to evaluate the calcium metabolic status of patients may enable early detection and improved clinical management of osteoporosis, multiple myeloma, and cancer metastatic to the bone. It has been estimated that as much as 30% of the population may benefit from this test and this could lead to better quality of life and lower medical care costs. Multiple small business opportunities may be enabled by development of an affordable and easy to use analytical platform, versus the multi-million dollar facilities needed for AMS-based 41Ca.